We seek to understand the role of phagocytes in immune function through examination of the consequences of immune defects. Our major focus is on chronic granulomatous disease (CGD), which is caused by defects in the enzyme NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. We have a comprehensive portfolio involving patients, animals, and laboratory specimens. We have continued our exploration of the seroepidemiology of Granulibacter bethesdensis, a novel Gram negative organism with a host range limited to CGD. We have confirmed a seropositivity rate of almost 75% in CGD patients, but an impressive 25% in normal individuals (J Infect Dis. 2012 Sep;206(6):943-51). Identification of the genetic and cellular basis of hyper-IgE recurrent infection syndrome (HIES or Job's syndrome), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities, as STAT3 has informed broad areas of investigation. With NIAID, NIAMS and extramural collaborators we have identified abnormalities in other cytokines downstream of STAT3, most notably IL-17, which is profoundly low in cells from Job's syndrome patients. Collaborating with investigators in NIAMS we have created a mouse model of STAT3 deficiency which has impaired wound healing and staphylococcal control. Collaborating with investigators in NHLBI we continue to study vascular endothelial cells from patients with STAT3 deficeincy in vitro, deriving endothelial and muscle cells from STAT3 deficient patients that have shown impaired chemokine production. Recently we identified novel defects in the scaffolding protein WDR1/AIP1. Interestingly enough, we have found the same defect in children seen here over the last 25 years with identified mutations in the same gene. These combined approaches continue to be productive and help us understand innate immunity and inflammation. These studies will help us understand several different infections, including filamentous fungal infections, at a molecular genetic and functional level.